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Mechanisms relating obesity to insulin resistance and the metabolic syndrome

MECHANISMS RELATING OBESITY TO INSULIN RESISTANCE
AND THE METABOLIC SYNDROME
by
Stella P. Kim
_____________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHYSIOLOGY AND BIOPHYSICS)
May 2007
Copyright 2007 Stella P. Kim

Insulin resistance has long been a distinguishing characteristic and major contributor in the pathogenesis of type 2 diabetes. Although there is no single cause for the development of insulin resistance, it is highly associated with increased body weight and adiposity. Insulin resistance can manifest as both a decrease in insulin's ability to suppress glucose production by the liver and stimulate glucose uptake into peripheral tissue. The first set of studies in this dissertation examined the relative development of hepatic and peripheral insulin resistance associated with obesity and found that after 12 weeks of an isocaloric, moderate fat diet, there was only a moderate degree of peripheral insulin resistance. However, there was a complete inability of insulin to suppress glucose production, suggesting that insulin resistance of the liver may be the primary defect in obesity associated insulin resistance.; During insulin resistance, glucose homeostasis is maintained by compensatory hyperinsulinemia. By examining the longitudinal changes in both insulin secretion and first-pass hepatic insulin extraction over 12 weeks of a fat diet, it was found that insulin secretion substantially increased at week 6, but returned to pre-diet levels by week 12. However, peripheral hyperinsulinemia was maintained due to a significant decrease in first-pass hepatic insulin extraction at week 12. These results suggest that changes in first-pass hepatic insulin extraction may provide a secondary physiological mechanism to preserve pancreatic beta-cell function during chronic insulin resistance.; It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels which then signal for compensatory hyperinsulinemia. But when obesity is induced by fat-feeding in the dog model, there is development of insulin resistance and fasting hyperinsulinemia despite constant fasting FFA and glucose. By examining the plasma profiles of FFA, glucose and other hormones over a 24-hour period, it was found that after six weeks of fat-feeding, there was a highly significant increase in the nocturnal levels of FFA. 24-hour glucose levels remained unchanged. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia.

MECHANISMS RELATING OBESITY TO INSULIN RESISTANCE
AND THE METABOLIC SYNDROME
by
Stella P. Kim
_____________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(PHYSIOLOGY AND BIOPHYSICS)
May 2007
Copyright 2007 Stella P. Kim